This project is focused on examining the ability of immune therapy to reverse the impairment in host immune function that occurs in protracted sepsis. Sepsis is the most common cause of death in most intensive care units and the 10th leading cause of overall mortality in the United States. Although early deaths in sepsis are often due to excessive inflammation, sepsis evolves to a highly immunosuppressive state. The underlying hypothesis of the present proposal is that many of the deaths occurring later in the course of sepsis are due to the resultant immunosuppression and that therapy that augments host immunity will improve survival. This application examines two novel drug candidates, i.e., IL-7 and anti-programmed cell death one (PD-1) as potential immune enhancing therapies of sepsis. IL-7 is cytokine that acts at numerous levels to improve host immunity. Its major actions are on CD4 and CD8 T cells. IL-7 has shown efficacy in viral, bacterial, and fungal infections. A second immunotherapeutic agent that will be tested is anti-PD-1 antibody. PD-1 is a cell receptor that is upregulated on lymphocytes in sepsis and causes inhibition of cell function. Antibodies to PD-1 have improved survival in several infectious models. IL-7 and anti-PD-1 antibody will be tested for their ability to improve survival in clinically relevant animal models f sepsis. In addition, studies will also examine the ability of IL-7 and anti-PD-1 to improve white blood cell function in septic patients. The results of this project will lead to a better understanding of host immunity in sepsis and may provide insight into potential therapies of this highly lethal disorder.